Histone N-terminal tails are extensively modified by a plethora of post-translational modifications, including histone methylation. Histone methylation has been implicated in multiple biological processes including heterochromatin formation, Xinactivation, genomic imprinting and silencing of homeotic genes. Methylation occurs on both lysine (K) and arginine (R) residues. Multiple K residues on the tails of histone H3 and H4 have been shown to be sites for methylation (mono-, di, and tri-methylation). Methylation at these sites has been linked to transcriptional activation and repression, as well as DNA damage response, indicating a widespread role for histone methylation in various aspects of chromatin biology. Unlike other histone modifications such as acetylation, methylation has long been considered a “permanent” modification. Our identification of the first histone demethylase LSD1 disproved this dogma, and suggested that histone methylation is dynamically regulated by both histone methylases and demethylases. Importantly, we have recently identified another large family of new histone demethylases (JmjC) that specialize in demethylating lysine trimethylation. Collectively these findings suggest that all three methylation states of the lysine residue (mono-, di- and trimethylation) can be reversed enzymatically. Our findings firmly established the notion that histone methylation is dynamically regulated by both histone methylases and demethylases. We are currently addressing the issues of mechanisms and biology of these newly identified histone demethylases in genetically tractable model organisms such as S. pombe, C. elegans and zebrafish. We are also exploring potential disease connections of these newly identified chromatin regulators. Finally, we are continuing our screens for new histone demethylases and are also using the assays established in the lab to search for potential DNA demethylases.

What are the functions of the various modifications that take place on the histone tails? One model suggests that these modifications (or lack thereof) serve as platforms for the recruitment of additional regulatory machineries that impact local chromatin structure and function. In fact, cells have dedicated significant resources to developing ways of recognizing histone tail modifications as evidenced by the recent identification of multiple protein modalities dedicated to recognizing various histone methylation marks. A challenge is to understand how combinatorial modifications on the histone tails are recognized, which is another area of focus of our lab.